Pharmacology 4: Interventions in Acute Inflammation

Question 1

What are Eicosaoids?

Answer 1

Eicosanoids are signalling molecules which exert control during inflammation and act as messengers in the CNS. 4 main types: prostaglandins (PG), prostacyclin, thromboxanes (Tx), and cysteinyl leukotrienes (LTs).

Question 2

How are prostaglandins (PG), prostacyclin, thromboxanes (Tx), and cysteinyl leukotrienes (LTs) formed?

Answer 2

They are formed from phospholipids. Phospholipids are converted to arachidonic acid (AA) using Phospholipase A₂. Eicosanoids are then formed from AA by two pathways: one that uses cyclooxygenase (COX) (making PR, prostacyclin and Tx) and the other that uses 5-lipoxygenase (making cysteinyl LTs)

Question 3

What are the actions fo eicosanoids in the inflammatory reaction?

Answer 3

Question 4

What are the different therapeutic strategies against inflammation?

Answer 4

• Non-steroidal anti-inflammatory drugs (NSAIDs)
  
  • Paracetamol (unique NSAID)
• Glucocorticoids
• Disease modifying anti-rheumatic drugs (DMARDS)
• Anti-cytokine therapy
• Anti-histamines

Question 5

How do NSAID’s worK?

Answer 5

NSAIDs work by inhibiting COX-1 and COX-2 enzymes, thereby reducing the synthesis of prostaglandins, prostacyclin and thromboxanes.

Question 6

Out of Cox-1 and Cox-2, which is constitutive and which is only inducible during inflammation?

Answer 6

Cox-2 inflammation, Cox-1 constitutive

Question 7

What can NSAID’s be as inhibitors?

Answer 7

• Irreversible inhibitors e.g. aspirin
• Competitive inhibitors – most NSAIDs
• Reversible non-competitive inhibitors (paracetamol)

Question 8

What are the effects of NSAID’s and how do they work?

Answer 8

• Anti-inflammatory – Prostaglandins produce vasodilation, increased vascular permeability and oedema. NSAIDs inhibit prostaglandin synthesis (by inhibiting cyclooxygenases) thereby limiting this part of the inflammatory reaction. NSAIDs have little effect on other mediators.
• Anti-pyretic - E type prostaglandins (PGE’s) are produced in response to IL-1 and are responsible for elevating the hypothalamic set point for temperature (fever). NSAIDs inhibit the synthesis of this mediator, reducing fever (will not affect heat stroke)
• Analgesic – Prostaglandins do not directly cause pain but instead potentiate pain by sensitizing nociceptive nerve endings to other mediators such as histamine and bradykinin. Hence, NSAIDs can reduce pain produced by inflammation by limiting the synthesis of prostaglandins.

Question 9

What are some side-effects of NSAID’s and why?

Answer 9

GIT- Dyspepsia (nausea, vomitting) + Ulcer formation

PGE2 and PGI2 normally inhibit gastric acid secretion, increase muscousal blood flow and have a cytoprotective effect

Renal- Renal Damage

Inhibition of PGE2 and PGI2 mediated vasodilation in the renal medulla and glomeruli

Other- Allergic Reaction + bronchospasm

Question 10

Why are COX-2 inhibitors sometimes more preferable?

Answer 10

Because COX1 inhibition leads to side effects, COX-2 specific inhibitors are preferable. COX-2 enzymes have wider channels and hence COX-2 specific inhibitors are larger molecules which cannot bind to COX-1.

COX-2 selective inhibitors (coxibs) have similarly positive effects to non-specific NSAIDs, but have no cardioprotective effects and are associated with a higher incidence of cardiovascular thrombotic events. E.g. Celecoxib, etoricoxib, meloxicam, rofecoxib

Question 11

What are some common COX-1 drugs?

Answer 11

e.g. Aspirin (acetylsalicylic acid)

• Non-selective inhibitor of both COX isoforms
• Irreversibly inhibits COX and inhibits platelet aggregation
• Used to manage mild-moderate pain (analgesic properties)
• Used to treat cardiovascular disorders (antiplatelet properties)
• Adverse effects, particularly of the GIT
• Low does acceptable for pain management; high does necessary for ant inflammation is too dangerous

e.g. Ibuprofen and other non-selective NSAIDs

• Generally reversible COX inhibitors
• Used to treat mild to moderate pain and inflammation
• Adverse side effects, particularly of the GIT and kidneys (glomerular filtration rate)

Question 12

What are some common COx-2 inhibitors?

Answer 12

. Paracetamol (acetaminophen)

• Analgesic, anti-inflammatory and anti-pyretic effects
• Reversible, non-competitive inhibitor
• Preferential for COX-2
• Side effects – no GIT or renal side effects but can cause hepatotoxicity

e.g. topical opthalmic NSAIDs (diclofenac and ketorolac)

• Used to treat photophobia, corneal abrasions, post-operative inflammation, allergy inflammation
• Often beneficial to administer drugs at the target site → fewer side effects because of lower dose

Question 13

An 18 year old student with a history of peptic ulcer has developed a fever of 39c and decides to take some OTC aspirin to reduce her temperature. Is apirin the best choice?

Answer 13

No. Paracetamol would have been better.

Question 14

A 42 year old man with a known aspirin sensitivity was given diclofenac eyedrops to treat allergic conjunctivitis. Two hours after the first day of dicolfenac, coughing and wheezing developed and worsened overnight. What is the most likely cause of this?

Answer 14

It is a Cox-1 inhibitor NSAID, which leads to an increase in the amount 5-lipoxygenase pathway, which leads to more leukotriens which a bronchoconstrictors.

Question 15

What is, and what is the function of Glucocorticoids?

Answer 15

• Anti-inflammatory and immunosuppressant
• have a broad spectrum of action and there many side effects
• Are used in the treatment of (among others)
  
  • rheumatoid arthritis
  • inflammatory bowel conditions
  • bronchial asthma
  • inflammatory skin conditions

Question 16

How do glucocorticoids act?

Answer 16

Glucocorticoids act by inhibiting the phospholipase A₂ enzyme, therebye inhibiting arachidonic acid formation and reducing production of eicosanoids. They can also act secondarily on just the COX.

Question 17

What are the effects of of glucocorticoids?

Answer 17

• Anti-inflammatory – Phospholipase A₂ inhibition reduces the formation of both prostaglandins and leukotrienes, which are important inflammatory mediators. Glucocorticoids also inhibit the induction of COX-2 enzymes
• Immunosuppression – inhibit the accumulation of neutrophils and monocytes. decreases:
  
  • antigen processing by macrophages (phagocytosis)
  • T helper cell function
  • Antibody production
  • Production of IL-2

Question 18

What are the side effect of GC?

Answer 18

Side effects:

• Suppression of the immune system
• Altered bone metabolism leading to osteoporosis
• Impaired wound healing
• Development of diabetes and peptic ulcers
• Growth suppression in children
• Cushing’s syndrome

Question 19

What are Disease Modifying Anti-rheamatic drugs?

Answer 19

This is a group of unrelated drugs defined by their use in slowing down the progression of rheumatoid arthritis. Many of these are highly toxic and lose their effects the longer patients take them, so patients are rotated through the drugs. For many of these, we do not know the long term side effects.

Question 20

What is anti-cytokoine therapy?

Answer 20

Anti-cytokine agents are biological preparations that target the action of TNF-α. Examples include infliximab and etanercept.

Another form of biological therapy is monoclonal antibodies against a chain of the IL-2 receptor. E.g. basiliximab, daclizumab

Question 21

What are anti-histamines?

Answer 21

H₁ receptor antagonists. Used clinically:

• To treat allergic reactions
• Antimeitics for motion sickness
• Sedation

e.g. mequitazine, fexofenadine, cetirizine